Whole-Body Molecular Map Explains Why Exercise Is So Good For You

Exercise not only improves muscle strength, improves heart health, and lowers blood sugar levels, but also a host of other health benefits. But how does regularly running on a treadmill, cycling up a steep hill or a brisk walk at lunchtime produce such a dizzying array of health benefits?

We are closer to answering this question thanks to a new, extensive study conducted by Stanford Medical School. Researchers took nearly 10,000 measurements in nearly 20 tissue types to examine the effects of eight weeks of endurance exercise in laboratory rats trained to run on rodent-sized treadmills.

Their findings highlight the dramatic effects of exercise on the immune system, stress response, energy production and metabolism. They found significant connections between exercise, molecules and genes that are already known to play a role in a variety of human diseases and tissue repair.

The study is one of a series of papers published May 1 by members of a multidisciplinary research team designed to lay the foundation for understanding—at the whole-body and molecular level—how our tissues and cells respond to exercise.

“We all know that exercise is good for us,” says pathology professor Stephen Montgomery, Ph.D. “But we know little about the molecular signals that occur throughout the body when people exercise, or how they may change with exercise. Our study is the first to look at molecular changes on a whole-body scale, from proteins to genes, metabolites, fats and energy production. This is the most extensive profiling of the effects of exercise to date, and it creates an important map of how exercise changes the body."

Montgomery, who is also a professor of genetics and biomedical data science, is senior author of the paper published in Nature.

A coordinated view of exercise

Researchers involved in the study and other simultaneous publications are part of a national group called the Molecular Transducers of Physical Activity Consortium, or MoTrPAC, organized by the National Institutes of Health. This initiative was launched in 2015 to study in detail how exercise improves health and prevents disease.

The Stanford Medicine team did most of the heavy lifting, studying the effects of eight weeks of endurance training on the expression of genes (transcriptome), proteins (proteome), fats (lipidome), metabolites (metabolome), and the pattern of chemical marks placed on DNA ( epigenome), immune system, etc.

They conducted 9,466 analyzes across multiple tissues from rats that were trained to run increasing distances and compared the results with those of rats that lounged in their cages. They paid particular attention to leg muscles, heart, liver, kidneys and white adipose tissue (a type of fat that accumulates as weight increases); other tissues included lungs, brain and brown adipose tissue (a more metabolically active type of fat that helps burn calories).

The combination of multiple assays and tissue types yielded results in the hundreds of thousands for non-epigenetic changes and more than 2 million different changes in the epigenome. These results will keep scientists busy for years to come.

Although this study primarily served to create a database for future analysis, some interesting results have already emerged. First, they noted that the expression of 22 genes changed with exercise in all six tissues they focused on.

Many of these genes were involved in so-called heat shock pathways, which stabilize protein structure when cells are exposed to stress, including changes in temperature, infection or tissue remodeling. Other genes have been implicated in pathways that lower blood pressure and increase the body's sensitivity to insulin, which lowers blood sugar.

The researchers also noted that the expression of several genes associated with type 2 diabetes, heart disease, obesity and kidney disease was reduced in rats who exercised compared to their sedentary counterparts, clearly indicating a link between their research and human health.

Gender differences

Finally, they found sex differences in how different tissues in male and female rats responded to exercise. Male rats lost about 5% of their fat after eight weeks of exercise, while female rats did not lose a significant amount of fat. (However, they maintained their initial body fat percentage, while the sessile females gained an additional 4% body fat over the course of the study.)

But the biggest difference was observed in gene expression in the rats' adrenal glands. After a week, genes associated with the production of steroid hormones such as adrenaline and energy production increased in male rats but decreased in female rats.

Despite these early, tempting associations, researchers caution that the science of exercise is far from complete. Rather, this is just the beginning. But the future looks promising.

“In the long term, it is unlikely that we will find one magic intervention that will replicate everything that exercise can do for a person,” Montgomery said. “But we can move closer to the idea of precision exercise—tailored recommendations based on a person's genetics, gender, age or other medical conditions to achieve beneficial whole-body responses.”